Natural products for schizophrenia

The natural D2 antagonist/D1 agonist L-stepholidine [1], may offer relief of positive symptoms, negative symptoms and deficits in working memory [2]. In vitro, D1 agonism has been disputed, recent research indicating that it is a pan-dopamine receptor antagonist [3].

L-tetrahydropalmatine – a D1/D2 antagonist (with multiple relevant pharmacological targets, including affinity for the sigma-1 receptor [4], may offer some benefit but research into its use in schizophrenia is lacking. “L-tetrahydropalmatine (l-THP), has robust anti-inflammatory properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, clozapine” [link]

Schizophrenia is a devastating and complex illness, with multiple symptom and behavioral manifestations. Antipsychotic medications are the mainstay of treatment; however, many patients only partially respond to treatment. Development of new treatment has not progressed rapidly, in part, because the underlying etiopathophysiology of the illness is not well understood. To date, all pharmacological treatments approved for use in schizophrenia involve primary modulation of the dopamine system. Many agents without dopamine action have failed to demonstrate efficacy. There is growing evidence that schizophrenia may be, in part, due to an inflammatory process and pharmacological treatment approaches that decrease inflammation have shown promise. Thus, treatments that may have anti-inflammatory properties (e.g., TNF-alpha inhibition), but also possess dopamine modulation may prove to be beneficial. This novel medication, l-tetrahydropalmatine (l-THP), has robust anti-inflammatory properties, particularly TNF-alpha and ICAM inhibition; has antiprotozoal activity; and possesses an antipsychotic-like pharmacological profile of D1, D2 and D3 receptor antagonism. The high affinity of l-THP for D1 versus D2 receptors distinguishes it from first generation antipsychotics and its D1 to D2 ratio resembles that of the superior antipsychotic, clozapine. Also, an almost identical compound, l-stepholindine (l-SPD), demonstrates robust antipsychotic activity in humans (both positive and negative symptoms) and is currently used clinically in China.

l-THP has been used for over 40 years clinically in China, has a good safety profile to date, and represents a novel and exciting mechanism for schizophrenia treatment. Initial safety data from our phase I study of l-THP (20 healthy controls) shows excellent tolerability and lack of any substantial side effects. L-THP has been tested in outpatient drug abuse trials for 4 weeks with good safety data, (Hu et al 2006, Yang et al 2003). Yang et al (2003) randomized this medication in over 120 participants for 4 weeks with 4 week observation without any notable side effects. We will test this compound (30 mg BID) as an adjunct treatment in a randomized, double-blind, 4-week trial, in which we will assess treatment efficacy, changes in peripheral cytokine concentrations, and, secondarily, antiprotozoal effects, (antibody titers to Toxoplasma gondii), an infection that is known to occur at higher rates in schizophrenia than healthy controls and may be related in part to the illness.

D1 receptor antagonist with a Ki of 94 ± 9 – 124 nM and an IC50 value of 166 nM [Note: this is contrary to clozapine which behaves as a D1 agonist (and/or has indirect effects leading to D1 receptor agonism), believed to partially account for its ‘superior’ efficacy as an antipsychotic]

D2 receptor antagonist with a Ki of 388 nM and an IC50 value of 1.47 μM

In addition to the antagonism of postsynaptic dopamine receptors, inhibition of presynaptic autoreceptors by THP leads to increased dopamine release, which is probably attributed to lower affinity towards D2 receptors.

Potently inhibits 5-HT1A with IC50 of 374 nM and Ki of 340 nM

Interacts with a number of other receptor types, including α-1 adrenergic receptors, at which it functions as an antagonist, and γ-aminobutyric acid receptors, at which it facilitates γ-aminobutyric acid binding through positive allosteric effects.

Attenuates the rewarding effects of drugs of abuse, including stimulants and opioids. It may be an effective anti-addiction therapy.

Modified from Jung et al. 2015: Absorption of THP from the GI tract seems almost complete, as GI24 h values were negligible. Most of the administered dose of THP is eliminated via non-renal clearance. A previous pharmacokinetic study of THP also reported negligible recovery of unchanged THP in urine and bile (1.48% and 0.4% of the administered THP dose) following oral administration of 40 mg/kg THP, and identified three O-desmethyl metabolites. THP is reportedly metabolized predominately by CYP3A1/2 and CYP1A2 in rat liver microsomes. The F values of THP are reportedly low: 2.5–17.8% for THP following oral administration of various formulations of Corydalis rhizome extracts at doses containing ca. 12 mg/kg THP.

Brain/Periphery (Br/P) ratios of THP were greater than unity (approximately 2–4) at 30, 120, and 360 min after single and multiple oral administration. The maximum concentrations of THP in brain were observed at 30 min after administration. These results suggest that THP passes through the blood-brain barrier. A previous study examining the distribution of THP following oral administration of a 40 mg/kg dose also demonstrated that Br/P ratios reach a maximum of approximately 5.0 after 5–30 min in all brain regions, except the hippocampus, where the ratio reached a maximum of 3.2 at 2 h, confirming that THP crosses the blood–brain barrier rapidly. Intravenous administration of THP (1–10 mg/kg) caused central nervous dopamine D2 receptor antagonism and induced hypotension and bradycardia.

Multiple oral administrations of an extract for 7 d (equivalent to 0.77 mg/kg/d as THP) did not result in accumulation of THP in plasma or brain. The maximum concentrations of THP in the brain were observed at 30 min after the last oral treatment; 131 ng/g for THP which is much lower than the IC50 values for antagonism of GTPγS binding to dopamine D2S receptor by THP [1.32 µM (469 ng/mL)]

Their research indicates that human doses of 30mg may not be sufficient for central dopamine D2 receptor antagonism

Other alkaloids such as alstonine [6, 7] have demonstrated antipsychotic activity in animal models. The MoA of alstonine is unique:

Alstonine is the major component of plant based remedies that traditional psychiatrists use in Nigeria. Alstonine is an indole alkaloid that has an antipsychotic experimental profile comparable with that of clozapine and is compatible with the alleged effects in mental patients. Representing a desirable innovation in the pharmacodynamics of antipsychotic medications, the evidence indicates that alstonine does not bind to D2 dopamine receptors (D2R) and differentially regulates dopamine in the cortical and limbic areas. The purpose of this study was to further investigate the effects of alstonine on D2R binding in specific brain regions using quantitative autoradiography (QAR) and its effects on dopamine (DA) uptake in mouse striatal synaptosomes. The effects of alstonine on D2R binding were determined in the nucleus accumbens and caudate-putamen using QAR in mice treated with alstonine doses that have antipsychotic effects. The effects of alstonine [3H]DA uptake were assessed in synaptosomes prepared from striatal tissue obtained from mice treated acutely or for 7 days with alstonine. Alstonine did not change the D2R binding densities in the studied regions. DA uptake was increased after acute (but not after 7 days) treatment with alstonine. Consistent with the alstonine behavioral profile, these results indicate that alstonine indirectly modulates DA receptors, specifically by modulating DA uptake. This unique mechanism for DA transmission modulation contributes to the antipsychotic-like effects of alstonine and is compatible with its behavioral profile in mice and alleged effects in patients. These results may represent an innovation in the antipsychotic development field.

Cholinergics

Consumption of Betel nut is associated with decreased positive symptoms in users with schizophrenia [8]. Arecoline, a constituent alkaloid may confer benefits via mAChR agonism. Similarly, nicotine use – particularly of tobacco – is extremely common in schizophrenics, offering reductions in negative symptoms and cognitive benefits to the user. nAChR agonists and positive allosteric modulators are promising leads for future therapeutics. Galantamine, acting as an AChE inhibitor and nAChR PAM, may offer some benefits, similarly to donepezil [9].

Adjunctive treatment with galantamine improved memory and attention in patients with schizophrenia who were stabilised on risperidone [a]

Despite some limitations – particularly related to bioavailability – supplementation with curcumin may be of benefit. A clinical trial is underway to determine if curcumin nanoparticles will improve behavioral measures and biomarkers of cognition and neuroplasticity in patients with schizophrenia.

Cannabidiol is also promising: “A compound found in Cannabis sativa can treat schizophrenia as effectively as antipsychotic medications, with far fewer side effects, according to a preliminary clinical trial. Researchers led by Markus Leweke of the University of Cologne in Germany studied 39 people with schizophrenia who were hospitalized for a psychotic episode. Nineteen patients were treated with amisulpride, an antipsychotic medication that is not approved in the U.S. but is comparable to other medications that are antipsychotic. The rest of the patients were given cannabidiol (CBD), a substance found in C. sativa that is thought to be responsible for some of its mellowing or anxiety-reducing effects. Unlike the main ingredient in marijuana, THC, which can produce psychotic reactions and may worsen schizophrenia, CBD has antipsychotic effects, according to previous research in both animals and humans. The use of CBD for schizophrenia is becoming more and more common. Studies from around the world are showing great promise. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD involve the striatum and temporal cortex that have been traditionally associated with psychosis [link].”

Berberine may offer benefit in the control of psychotic and depressive symptoms, along with metabolic side effects [13]. It has a broad range of CNS relevant pharmacological actions, including sigma-1 agonism. There are some limitations to its use, including bioavailability and difficulties in reaching active levels in the CNS. “The potential use in schizophrenia was suggested when berberine was found to act as a D2-receptor antagonist, although it was also noted that dopamine level was increased in the brain as partly responsible for its antidepressant mechanism. It is unclear if these influences on dopamine level and action may counter each other, diminishing the proposed antipsychotic effect. Future studies may also elucidate whether berberine will exacerbate extrapyramidal motor symptoms due to the blockade of D2 receptors. On the other hand, it was proposed that the anxiolytic effect of berberine resulted from its antagonism at 5-HT2 receptor. This finding may indicate less severe motor side effects, if there are any, when berberine is used as an antipsychotic since atypical antipsychotics also act via 5-HT2 receptor blockade. A possible advantage of berberine over other antipsychotics is its ability to inhibit prolyl oligopeptidases, the activity of which is elevated in psychosis and not targeted by antipsychotics at present.”

Low doses of lavender oil may be an effective adjunct therapy for anxiety. At 80+ mg/day – a dose used to effectively treat anxiety – orally administered lavender oil non-selectively reduces the calcium influx through several different types of voltage dependent calcium channels such as the N-type, P/Q-type and T-type [14]. This effect is similar to, but lacks the specificity of, pregabalin’s selective binding to P/Q type calcium channels at the α2δ subunit . Pregabalin has potential in treating anxious syndromes in schizophrenia and can be effective and tolerable [15] It may however increase clozapine serum levels [16] making lavender an intriguing alternative for some patients

Potentially of relevance to schizophrenia, researchers discovered that “…social contact deficits are reversed by resveratrol administration” emphasising a “prosocial role for this dietary phenol” and evoking “the possibility of developing new treatments for social dysfunctions.” [24]

Chelerythrine is a benzophenanthridine alkaloid present in the plant Chelidonium majus (greater celandine). It is a potent, selective, and cell-permeable protein kinase C inhibitor and “Improves PFC working memory” [25]

A small study found benefits from sulforaphane administration [27]: “Sulforaphane (SFN) is a molecule belonging to the isothiocyanate group of organosulfur compounds found in broccoli sprouts. It is known to have potent anti-oxidant and anti-inflammatory activity. Previously, we reported that SFN attenuated behavioral abnormalities in mice after administration of methamphetamine or phencyclidine, suggestive of a potential therapeutic potency in schizophrenia. Recently, we found that SFN improved cognitive deficits in phencyclidine-treated mice”.

High quality evidence shows that treatment with Ginkgo biloba in combination with antipsychotics improves total symptom severity to a greater extent than antipsychotics alone in people with chronic schizophrenia in studies conducted in China.

Moderate quality evidence suggests various traditional Chinese herbal medicines combined with antipsychotics may result in greater improvement in global state and mental state and better retention in treatment compared to antipsychotics alone.

Moderate to low quality evidence suggests traditional Chinese medicine (SuoQuan Wan) but may be more effective than doxepin (antimuscarinic) for reducing clozapine-induced hypersalivation and may cause less constipation.